Inflammatory response in the hippocampus of PS1M146L/APP751SL mouse model of Alzheimer's disease: age-dependent switch in the microglial phenotype from alternative to classic

J Neurosci. 2008 Nov 5;28(45):11650-61. doi: 10.1523/JNEUROSCI.3024-08.2008.

Abstract

Although the microglial activation is concomitant to the Alzheimer's disease, its precise role (neuroprotection vs neurodegeneration) has not yet been resolved. Here, we show the existence of an age-dependent phenotypic change of microglial activation in the hippocampus of PS1xAPP model, from an alternative activation state with Abeta phagocytic capabilities (at 6 months) to a classic cytotoxic phenotype (expressing TNF-alpha and related factors) at 18 months of age. This switch was coincident with high levels of soluble Abeta oligomers and a significant pyramidal neurodegeneration. In vitro assays, using astromicroglial cultures, demonstrated that oligomeric Abeta42 and soluble extracts from 18-month-old PS1xAPP hippocampus produced a potent TNF-alpha induction whereas monomeric Abeta42 and soluble extract from 6- or 18-month-old control and 6-month-old PS1xAPP hippocampi produced no stimulation. This stimulatory effect was avoided by immunodepletion using 6E10 or A11. In conclusion, our results show evidence of a switch in the activated microglia phenotype from alternative, at the beginning of Abeta pathology, to a classical at advanced stage of the disease in this model. This change was induced, at least in part, by the age-dependent accumulation of extracellular soluble Abeta oligomers. Finally, these cytotoxic activated microglial cells could participate in the neuronal lost observed in AD.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aging*
  • Alzheimer Disease / complications*
  • Alzheimer Disease / pathology*
  • Amyloid beta-Protein Precursor / genetics
  • Analysis of Variance
  • Animals
  • CD11b Antigen / metabolism
  • CD3 Complex / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation / genetics
  • Glial Fibrillary Acidic Protein / metabolism
  • Inflammation / etiology*
  • Lectins / metabolism
  • Mice
  • Mice, Transgenic
  • Microglia / pathology*
  • Mutation / genetics*
  • Nitric Oxide Synthase Type II / metabolism
  • Phenotype
  • Presenilin-1 / genetics
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Amyloid beta-Protein Precursor
  • CD11b Antigen
  • CD3 Complex
  • Glial Fibrillary Acidic Protein
  • Lectins
  • Presenilin-1
  • Tumor Necrosis Factor-alpha
  • Nitric Oxide Synthase Type II